The mammalian olfactory system responds both to neutral odors, whose significance for the organism is assigned by learning, and to odors that elicit innate behaviors. A subset of olfactory sensory neurons expresses trace amine associated receptors (TAARs) that respond to volatile amines that are mostly aversive to rodents. We recently described the projection patterns of TAAR-expressing neurons (TRNs) to the olfactory bulb and examined the molecular mechanisms that control the expression of a single TAAR per TRN. Based on these findings, our overall hypothesis is that the TRNs constitute a distinct olfactory subsystem and that they integrate into hard-wired circuits that enable them to extract specific environmental cues and drive robust innate behavioral responses. Several predictions stem from this hypothesis: 1. TRNs are molecularly distinct from ORNs and they use specific mechanisms to ensure expression of a single receptor per neuron; 2. Activation of the TRNs is sufficient to elicit innate behavioral responses and, 3. The projections from the TAAR glomeruli are stereotyped and target central neural structures appropriate to aversive behavior responses. To test these predictions, we will conduct an interdisciplinary, multi-tiered approach that spans the molecular, neuroanatomical, neurophysiological and behavioral levels. At the molecular level, we will use unbiased approaches to unequivocally determine whether TRNs express only TAARs or co-express a subset of ORs. Further, we will definitively determine whether TRNs are molecularly committed to exclusively express TAARs, or can switch to express ORs upon choosing a deleted Taar gene. We will also analyze sorted populations of TRNs to identify repressive epigenetic marks and activating enhancer sequences that control expression of a single TAAR per TRN. Together, these studies will provide the molecular evidence for defining the TRNs as a distinct olfactory subsystem. At the anatomical level, we will map the projections from the TAAR glomeruli in the bulb to higher olfactory centers in the brain. We predict that these projections will be stereotyped and these glomeruli may project predominantly to the amygdala. At the systems/behavioral level, we will determine the behavioral consequences of selective optogenetic activation of TRNs, following systematic characterization of the optimal stimuli for driving bulb responses. These experiments will test whether TAAR circuits are hard wired to induce innate behavioral responses such as sniffing, and hard wired to assign aversive valence. Our studies are the first to examine innate responses to aversive olfactory stimuli in the context of known receptors and ligands. They will shed light on the molecular and anatomical substrate of innate responses to aversive stimuli, and provide foundation for direct links between molecular and anatomical organization and behavioral outcomes. Understanding the neural mechanisms mediating the conversion of sensory information to eliciting innate behaviors may provide new insight into the underpinnings of several psychiatric conditions.